Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive EGFR-mutant Non–small Cell Lung Cancer
- Authors
- Yu, H.A.[Yu, H.A.]; Paz-Ares, L.G.[Paz-Ares, L.G.]; Yang, J.C.-H.[Yang, J.C.-H.]; Lee, K.H.[Lee, K.H.]; Garrido, P.[Garrido, P.]; Park, K.[Park, K.]; Kim, J.-H.[Kim, J.-H.]; Lee, D.H.[Lee, D.H.]; Mao, H.[Mao, H.]; Wijayawardana, S.R.[Wijayawardana, S.R.]; Gao, L.[Gao, L.]; Hozak, R.R.[Hozak, R.R.]; Chao, B.H.[Chao, B.H.]; Planchard, D.[Planchard, D.]
- Issue Date
- 15-Feb-2021
- Publisher
- American Association for Cancer Research Inc.
- Citation
- Clinical Cancer Research, v.27, no.4, pp.992 - 1003
- Indexed
- SCIE
SCOPUS
- Journal Title
- Clinical Cancer Research
- Volume
- 27
- Number
- 4
- Start Page
- 992
- End Page
- 1003
- URI
- https://scholarworks.bwise.kr/skku/handle/2021.sw.skku/1739
- DOI
- 10.1158/1078-0432.CCR-20-1690
- ISSN
- 1078-0432
- Abstract
- Purpose: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non–small cell lung cancer (NSCLC). Patients and Methods: This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-nave. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. Results: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6–21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5–19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification. Conclusions: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC. © 2020 American Association for Cancer Research.
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